Gene therapy is amenable for correcting inborn errors of metabolism, as well as for the treatment of cancer and HIV.Lentiviral vectors are among the most efficient tools for gene delivery into mammalian cells. Our long-term goal is to develop a targetable gene delivery system that can transduce a specific cell type, a specific tissue or a specific organ after intravenous adminstration. Our preliminary studies have uncovered a truly targetable lentiviral vector system for gene delivery. The experimental focus of this proposal is to evaluate the therapeutic potential of this method for in vivo targeting. The first specific aim is to study the molecular mechanism of targeted infection by engineered recombinant viruses. Understanding this process should lead to identification and design of new molecules for targeting. The second specific aim is to perfect the strategy to prepare lentiviruses, which will greatly enhance the efficacy of virus preparation. The third specific aim is to explore novel molecules for targeting lentiviral vectors, which will expand our ability to manipulate lentiviruses for targeting. The fourth specific aim is to explore the utility of targeted gene delivery using antibody- and SCF-bearing lentiviruses. These studies build upon our novel finding that viruses displaying membrane-bound antibodies or stem cell factor (SCF) can specifically infect cells expressing cognate antigens or SCF receptors. Various experiments are proposed to assess the therapeutic implications of this novel targeting strategy to treat HIV and cancer in animal models. Taken together, these novel studies will enlarge the therapeutic potential of targeted gene delivery to treat a diverse range of diseases, as well as advance our undstanding of viral infection.